About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

March 15, 2010

Tricor's Troubles

Posted by Derek

It's easy to lose sight of what a drug is supposed to do. Many conditions come on so slowly that we have to use blood chemistry or other markers to see the progress of therapy in a realistic time. And over time, that blood marker can get confused with the disease itself.

To pick one famous example, try cholesterol. Everyone you stop on the street will know that "high cholesterol is bad for you". But the first thing you have to do is distinguish between LDL and HDL cholesterol - if the latter is a large enough fraction of the total, the aggregate number doesn't matter as much. And fundamentally, there's not a disease called "high cholesterol" - that's a symptom of some other cluster of metabolic processes that have gone subtly off. And the endpoint of any therapy in that field isn't really to lower the number in a blood test: it's to prevent heart attacks and to extend healthy lifetimes, mortality and morbidity. As we're seeing with Vytorin, it may be possible to drop the numbers in a blood test but not see the benefit that's supposed to be there.

Another example of this came up over the weekend. The fibrates are a class of drugs that change lipid levels, although the way they work is still rather obscure. They're supposed to be ligands for the PPAR-alpha nuclear receptor, but they're not very potent against it when you study that closely. At any rate, they do lower triglycerides and have some other effects, which should be beneficial in patients whose lipids are off and are at risk for cardiac problems.

But are they? Type II diabetics tend to be people who fit that last category well, and that's where a lot of fenofibrate is prescribed (as Abbott's Tricor in the US, and under a number of other names around the world). A five-year study in over five thousand diabetic patients, though, has just shown no difference versus placebo. Again, there's no doubt that the drug lowers triglycerides and changes the HDL/LDL/VLDL ratios. It's just that, for reasons unknown, doing so with fenofibrate doesn't seem to actually help diabetic patients avoid cardiac trouble.

Mortality and morbidity: lowering them is a very tough test for any drug, but if you can't, then what's the point of taking something in the first place? This is something to keep in mind as the push for biomarkers delivers more surrogate endpoints. Some of them will, inevitably, turn out not to mean as much as they're supposed to mean.

Well, statins are pretty good at lowering LDL and preventing heart attacks, which has no doubt caused a lot of companies to pursue other strategies for altering lipid profiles.
But statins' pleiotropic effects may have a lot to do with their benefits in cardiovascular disease. For instance, improvements in mortality are seen before any real change in lipid profile, but this area still isn't as well-studied as it might be (putting 'statins pleiotropic effects' into Pubmed pulls out almost as many reviews as original papers).
As you say Derek, it's important to keep your eye on the ball of the disease being treated.

So should all FDA approvals for drugs that passed on surrogate endpoints be provisional, requiring a showing of reduced mortality ("delta death") after launch on the market? Is it possible to run such a study (in which has the participants would get a placebo, rather than the approved drug)?

Ah surrogate endpoints. I would have thought that approach would have died after the AZT fiasco for AIDS years ago. AIDS patients have a decline in the number of lymphocytes carrying a particular surface marker (CD4), and when this number gets below a certain point, the patient is almost certainly likely to get into very serious trouble with infection. AZT definitely raised the number of cells carrying CD4 but had little or no effect on survival.

People who own yachts survive longer than those who don't. Giving everyone a yacht is not a solution to the health problems of the populace. This is why surrogate endpoints are dangerous when applied simplistically.

The NYTimes today has the results of 3 studies in type II diabetics, where manipulating a surrogate had zero or negative effects on survival.

Surrogates are certainly reasonable things to look at and manipulate, but there is just no substitute for the data that comes after they've been manipulated in large numbers of people

It's clear there are many things going on in diabetes and other metabolic disorders that we simply do not understand.

It's also very likely that there are new drugs, yet undiscovered, that could be developed and that *will* improve mortality and morbidity.

It's too bad the entire pharma industry is now run by dyscompetents, incompetents, and other management fools who - by the very sight of comments on this blog on layoff threads - have so demoralized the very soul of drug discovery (chemists) that these new drugs are unlikely to be developed at all.

The industry in its current anti-intellectual, "lay them off and watch the stock price rise", short term idiocy death spiral is basically good for nothing except money games.

Vaguely related: we had a compound just about ready for IND, when a long-term study on a marketed drug acting by the same mechanism came out. The marketed stuff shortened survival slightly (but significantly, per the statistics), but the patients' "quality of life" improved, according to the (surviving!) patients' comments. What to do? Our management decided to stop development immediately - "doctors have long memories" or words to that effect....

In addition to hyperlipidemic disorders and diabetes PPARs are also being studied for the treatment of polycystic ovary syndrome, psoriasis, autism, and even drug addiction. The full reach of this family of compounds is just being explored.

#8: I should have been more specific. This was for congestive heart failure, basically just symptomatic treatment. The patients said they felt better, were more active, and so on. Could be they were a little TOO active...

The Tricor result is not surprisng to anyone who has actually read the label, which notes multiple studies that showed no benefit in cardiovascular outcomes for fibrates in general. In fact, mortality trends repeatedly favored placebo. On the other hand fibrates were good at giving you gall stones. It's all in the official FDA-approved label. Incredibly, these facts have been consistently ignored for years (go figure). I guess free pens and mugs work.

The Framingham study evidence underlying the “lipid hypothesis” was never strong to start with. Since then a massive lipid lowering campaign has shown no effect on heart disease rates. While an elegant and seemingly intuitive hypothesis, more and more openly people are rightly questioning the wisdom of the cholesterol lowering campaign.

The side effects of statins are myriad, rhabdomyolysis, (muscle injury), liver damage, in Crestor's case kidney damage. Dr Duane Graveline an MD and former NASA astronaut has also compiled extensive data on a more rare statin side effect, global transient amnesia, which afflicted him and many others, he has written a book on it, "Lipitor thief of memory". http://healthjournalclub.blogspot.com/2009/11/statins-and-global-transient-amnesia.html

Don't forget co-enzyme Q depletion. All this while the "lipid hypothesis" is falling like a house of cards as decades of intensive lipid lowering efforts have done nothing to improve heart disease rates.

I believe the reference to morbidity improvements are associated with the benefits on eye disease, and amputations that have been observed with TriCor. It might appear that you don't live any longer but may in fact live a better quality life.